PROJECT SUMMARY Transposable elements, known colloquially as ?jumping genes,? constitute approximately 45% of the human genome. Cells utilize epigenetic defenses to limit transposable element jumping, including formation of silencing heterochromatin and generation of piwi-interacting RNAs (piRNAs), small RNAs that facilitate clearance of transposable element transcripts. Transposable element activation has recently been identified as a key mediator of neuronal death in tauopathies, a group of neurodegenerative disorders that are pathologically defined by deposits of tau protein in the brain. Using genetic approaches in Drosophila melanogaster models of tauopathy, a causal relationship was established between pathogenic tau-induced heterochromatin decondensation and piwi/piRNA depletion, active transposable element mobilization, and neurodegeneration. Transposable element activation responds to pharmacological inhibition, as 3TC, an FDA-approved, water- soluble nucleoside analog inhibitor of reverse transcriptase, suppresses transposable element mobilization and neuronal death in tau transgenic Drosophila. Transcripts of the human endogenous retrovirus (HERV) class of transposable elements, among others, were found to be elevated in postmortem brain tissue from human Alzheimer?s disease and progressive supranuclear palsy, a ?primary? tauopathy. Taken together, these studies identify heterochromatin decondensation, piwi/piRNA depletion and consequent transposable element activation as a novel, conserved, pharmacologically targetable, mechanistic driver of neurodegeneration in tauopathy. To advance toward our long-term goal of developing mechanism-based therapies for the treatment of human tauopathies, the core objectives of the current proposal are to 1) Test the hypothesis that transposable element causes neuroinflammation in tauopathy, 2) Test the hypothesis that transposable element activation occurs in mouse models of tauopathy, and 3) Test the hypothesis that transposable element activation occurs in neurons of human tauopathy. To address issues of causality, test hypotheses in brains of aged animals with functional neuronal networks, and determine relevance to human disease, we combine studies in Drosophila, mouse models of tauopathy, and postmortem human Alzheimer?s disease brain tissue. Successful completion of these studies will set the stage for future development of nucleoside analog reverse transcriptase inhibitors as a tauopathy therapeutic.